Proton Pump Inhibitor Initiation and Withdrawal affects Gut Microbiota and Readmission Risk in Cirrhosis

Bajaj, Jasmohan S.; Acharya, Chathur; Fagan, Andrew; White, Melanie B.; Gavis, Edith; Heuman, Douglas M.; Hylemon, Phillip B.; Fuchs, Michael; Puri, Puneet; Schubert, Mitchell L.; Sanyal, Arun J.; Sterling, Richard K.; Stravitz, Todd; Siddiqui, Mohammad Shadab; Luketic, Velimir A.; Lee, Hannah; Sikaroodi, Masoumeh; Gillevet, Patrick M.

doi:10.1038/s41395-018-0085-9

Cited by 102 publications

(94 citation statements)

References 31 publications

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“…In a cohort of 15 patients with decompensated cirrhosis, a 2‐week course of omeprazole (40 mg once daily) resulted in significantly increased abundances of Porphyromonadaceae and Streptococcaceae. Conversely, withdrawal of chronic unindicated PPI therapy in 15 patients with decompensated cirrhosis resulted in significantly decreased abundance of in Porphyromonadaceae, Streptococcaceae and Veillonellaceae …”

Section: Resultsmentioning

confidence: 99%

Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract—evidence from next‐generation sequencing studies

Macke

Schulz

Koletzko

et al. 2020

Aliment Pharmacol Ther

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Background: Proton pump inhibitors (PPI) are widely used to treat acid-related disorders of the upper gastrointestinal tract. However, large observational studies have raised concerns about PPI-associated adverse events. In recent years, data from next-generation sequencing studies suggested that PPIs affect the composition of the intestinal microbiota, while a balanced gut microbiome is essential for maintaining health.Aim: To review the available evidence from next-generation sequencing studies on the effect of PPIs on the intestinal microbiome and to discuss possible implications of PPI-induced dysbiosis in health and disease.Methods: A systematic review was conducted following the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. A PubMed query yielded 197 results. 19 publications met the prespecified eligibility criteria.Results: Twelve observational study cohorts with 708 PPI users and 11 interventional cohorts with 180 PPI users were included in the review. In most studies, PPI treatment did not affect microbiological richness and diversity, but was associated with distinct taxonomic alterations: In the upper gastrointestinal tract, PPI users showed overgrowth of orally derived bacteria, mostly Streptococcaceae (findings based on six independent cohorts with 126 PPI users). In faecal samples, PPIs increased multiple taxa from the orders Bacillales (eg, Staphylococcaceae), Lactobacillales (eg, Enterococcaceae, Lactobacillaceae, Streptococcaceae) and Actinomycetales (eg, Actinomycetaceae, Micrococcaceae), the families Pasteurellaceae and Enterobacteriaceae and the genus Veillonella. Taxa decreased by PPIs include Bifidobacteriaceae, Ruminococcaceae, Lachnospiraceae and Mollicutes (findings in faecal samples based on 19 independent cohorts with 790 PPI users). Conclusion: PPI use is associated with moderate alterations to upper and distal gut microbiota. The available data suggest that PPI-induced hypochlorhydria facilitates colonization of more distal parts of the digestive tract by upper gastrointestinal microbiota. MACKE Et Al 1 | INTRODUC TI ON: G A S TRI C ACID INHIB ITI ON AND ADVER S E EFFEC TS OF PPIS Gastric acid eliminates microorganisms, promotes the digestive process and facilitates the absorption of iron, calcium and vitamin B12. However, gastric acid also contributes to the development of mild and severe gastroduodenal pathologies. Proton pump inhibitor (PPIs) are the most effective therapy of acid-related diseases and are among the most commonly used drugs. 1 While generally considered a safe therapy, PPIs have been associated with numerous adverse effects in population-based observational studies conducted in recent years. These include cardiovascular and kidney disease, micronutrient deficiencies and osteoporosis, cognitive impairment and death. 2Most studies are retrospective and not hypothesis-driven in design, might be subject to significant confound and thus they cannot establish causality. 2,3 This is also the case for a recent study on ...

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Section: Resultsmentioning

confidence: 99%

Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract—evidence from next‐generation sequencing studies

Macke

Schulz

Koletzko

et al. 2020

Aliment Pharmacol Ther

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“…Different studies have shown that PPIs, by altering the gut microbiota, may increase the occurrence of spontaneous bacterial peritonitis and other bacterial infections in patients with cirrhosis . A recent American study demonstrated that PPIs modulate readmission risk and microbiota composition in cirrhosis, which respond to withdrawal .…”

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confidence: 99%

Proton Pump Inhibitors Are Associated With Minimal and Overt Hepatic Encephalopathy and Increased Mortality in Patients With Cirrhosis

Nardelli¹,

Gioia²,

Ridola³

et al. 2019

Hepatology

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Minimal hepatic encephalopathy (MHE) is a subclinical cognitive impairment frequently observable in patients with cirrhosis. Proton pump inhibitors (PPIs) can contribute to small‐bowel bacterial overgrowth, but no study has investigated the link between PPIs and MHE. We investigated the relationship between MHE and PPI use as well as the role of PPI use in the development of overt HE and survival. Consecutive patients with cirrhosis (n = 310) were included in the study and followed up for 14.1 ± 12.3 months. At entry, MHE was diagnosed when the Psychometric Hepatic Encephalopathy Score was ≤–4. Data were analyzed by logistic regression for the factors associated with MHE and by time‐related models for overt HE development and survival. At inclusion, 131 out of 310 patients with cirrhosis (42%) were affected by MHE. One hundred and twenty‐five patients (40%) were using PPIs. The variables independently associated with the presence of MHE were PPI use, previous overt HE, low albumin, low sodium, and age. During follow‐up, the development of overt HE was higher (64% versus 25%, P < 0.001) and overall survival lower (41% versus 81%, P < 0.001) in PPI users than in nonusers. Variables independently associated with the development of overt HE were PPIs, history of overt HE, low albumin, MHE, and age, while variables independently associated with mortality were PPIs, development of overt HE, Model for End‐Stage Liver Disease score, low sodium, and age. Conclusion: The study identifies a potentially removable factor associated with the presence of MHE and related to the development of overt HE and survival in patients with liver cirrhosis.

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“…Many medically approved drugs influence microbiome composition . In liver cirrhosis, PPI use has been described to alter microbiome composition, increase the rate of complications and negatively impact prognosis . We recently expanded this knowledge by describing the consequences of PPI‐induced dysbiosis and oralization of the faecal microbiome on inflammation, intestinal permeability and outcome in cirrhosis .…”

Section: Discussionmentioning

confidence: 99%

Disease severity and proton pump inhibitor use impact strongest on faecal microbiome composition in liver cirrhosis

Stadlbauer

Komarova

Klymiuk

et al. 2020

Liver International

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Background & Aims Compositional changes of the faecal microbiome in cirrhosis are well described and have been associated with complications and prognosis. However, it is less well known, which disease or treatment‐related factors affect microbiome composition most distinctively. Methods 16S rDNA sequencing data of 88 cirrhotic outpatients were investigated. Factors influencing microbiome composition were analysed by univariate and multivariate redundancy analysis. The association of the identified factors with changes in diversity and taxonomic composition was studied in depth using analysis of composition of microbiome, LDA‐effect size and least absolute shrinkage and selection operator regularized regression. Results Disease severity and aetiology, proton pump inhibitor (PPI) use, nutritional status, age and C‐reactive protein are significant explanatory variables for faecal microbiome composition in liver cirrhosis. Despite some taxonomic overlaps especially between disease severity and PPI use, we could show that the effects of disease severity, aetiology, PPI use and age are independent factors influencing microbiome composition also in subgroup analyses. Conclusion Our cross sectional system biology study identifies disease severity, aetiology, PPI use and age as independent factors that influence microbiome composition in liver cirrhosis. In chronic diseases with high morbidity, such as liver cirrhosis, precise patient metadata documentation is of utmost importance in microbiome analysis. Further studies with a higher sample size are necessary to validate this finding. Trial Registration Number: NCT01607528

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Proton Pump Inhibitor Initiation and Withdrawal affects Gut Microbiota and Readmission Risk in Cirrhosis

Abstract: PPIs modulate readmission risk and microbiota composition in cirrhosis, which responds to withdrawal. The systematic withdrawal and judicious use of PPIs is needed from a clinical and microbiological perspective in decompensated cirrhosis.

Cited by 102 publications

References 31 publications

Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract—evidence from next‐generation sequencing studies

Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract—evidence from next‐generation sequencing studies

Proton Pump Inhibitors Are Associated With Minimal and Overt Hepatic Encephalopathy and Increased Mortality in Patients With Cirrhosis

Disease severity and proton pump inhibitor use impact strongest on faecal microbiome composition in liver cirrhosis

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